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. 2025 Apr;17(5):331-338.
doi: 10.1080/1750743X.2025.2491300. Epub 2025 Apr 14.

Proton pump inhibitors reduce nivolumab efficacy in unresectable advanced or recurrent gastric cancer

Masahito Shibano  1 , Masaya Takahashi  1   2 , Hitomi Nakatsukasa  1 , Yusuke Ishigami  1 , Takahiro Toyokawa  3 , Koichi Taira  4 , Tomoya Kawaguchi  5 , Yasutaka Nakamura  1 , Hiroyasu Kaneda  5
Affiliations

Proton pump inhibitors reduce nivolumab efficacy in unresectable advanced or recurrent gastric cancer

Masahito Shibano et al. Immunotherapy. 2025 Apr.

Abstract

Background: Proton pump inhibitors (PPI) have been shown to decrease the efficacy of immune checkpoint inhibitors in patients with various cancer types. However, there are few reports on their effect on patients with gastric cancer (GC). Therefore, we investigated the efficacy of nivolumab in patients with GC receiving PPI.

Methods: This retrospective study analyzed data of patients who received nivolumab monotherapy for unresectable advanced or recurrent GC at Osaka Metropolitan University Hospital between September 2017 and December 2021. The primary and secondary endpoints were progression-free survival (PFS) and overall survival (OS), respectively. PPI use was defined as within 30 days before and after initiation of nivolumab monotherapy.

Results: Seventy-seven eligible patients were included in this analysis. PPIs were used in 33 patients, while 36 patients had a previous gastrectomy. Multivariate analysis revealed that only PPI use was an independent predictor of PFS (hazard ratio [HR] 1.93, 95% confidence interval [CI] 1.03-3.64, p = 0.042). Contrastingly, PPI use was not an independent predictor of OS.

Conclusion: PPIs may reduce the efficacy of nivolumab, and their use should be carefully considered in patients receiving nivolumab.

Keywords: Proton pump inhibitors; gastric cancer; microbiome; nivolumab; previous gastrectomy.

Plain language summary

Proton pump inhibitors (PPIs) are medicines that reduce stomach acid and are often used to treat gastric and duodenal ulcers. However, PPIs may make immune-based cancer treatments less effective in lung and urothelial cancers. It is still unclear how they affect gastric cancer (GC) patients, especially those who have had stomach surgery. We studied how PPI affects the effectiveness of nivolumab in these patients. We analyzed the records of 77 patients with advanced or recurrent GC who received nivolumab treatment at Osaka Metropolitan University Hospital between September 2017 and December 2021. Of these, 33 had used PPI, and 36 had undergoing stomach surgery. We examined how long patients lived without their cancer worsening (progression-free survival, PFS) and their overall survival (OS). Our findings showed that patients using PPI had a higher risk of cancer progression. However, PPI did not independently affect overall survival. Even in patients who had undergoing stomach surgery, those using PPI tended to have worse outcomes. These results suggest that PPI may reduce the effectiveness of nivolumab. Doctors should carefully consider the use of PPI in patients receiving nivolumab to ensure the best possible treatment outcomes.

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Conflict of interest statement

Dr. Kaneda has received lecture fees Chugai, MSD, Ono pharmaceutical, and Bristol-Myers Squibb. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

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